{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:33:25Z","timestamp":1790127205359,"version":"4.0.1"},"reference-count":62,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR\u2010TR1\u20102023\u201012377972"],"award-info":[{"award-number":["PNRR\u2010TR1\u20102023\u201012377972"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Mutations in isocitrate dehydrogenase 1 or 2 (\n                    <jats:italic>IDH1\/2<\/jats:italic>\n                    ) define a major subgroup of adult\u2010type diffuse gliomas and induce accumulation of D\u20102\u2010hydroxyglutarate, resulting in extensive DNA and histone methylation changes. This epigenetic reprogramming underlies the glioma CpG island methylator phenotype (G\u2010CIMP) and contributes to tumour lineage, differentiation state and clinical behaviour. DNA methylation profiling has consequently evolved from a research tool into an important ancillary method for CNS tumour classification, molecular subclassification and copy\u2010number analysis. This narrative review examines the biological basis, analytical platforms and clinical applications of DNA methylation profiling in IDH\u2010mutant gliomas. Particular attention is given to the distinction between research\u2010defined G\u2010CIMP\u2010high and G\u2010CIMP\u2010low states and classifier\u2010defined lower\u2010grade and high\u2010grade methylation subclasses. High\u2010grade signatures, including A_IDH_HG and G\u2010CIMP\u2010low, are associated with adverse genomic features and outcome but should not be considered interchangeable or used in isolation to assign CNS WHO grade. Their interpretation requires integration with histology and established molecular criteria, including homozygous\n                    <jats:italic>CDKN2A\/B<\/jats:italic>\n                    deletion. The review also discusses array\u2010based profiling, emerging Nanopore and long\u2010read approaches, computational quality control, and the integration of methylation data with genomic and transcriptomic alterations. Longitudinal studies indicate that a subset of IDH\u2010mutant astrocytomas undergoes methylation loss, copy\u2010number accumulation and altered cell\u2010state differentiation during progression, although these changes are not universal. The clinical relevance of\n                    <jats:italic>MGMT<\/jats:italic>\n                    promoter methylation is more context\u2010dependent than in IDH\u2010wildtype glioblastoma. Moreover, the INDIGO trial established the clinical activity of mutant IDH inhibition in selected Grade 2 gliomas but did not validate methylation class as a predictive biomarker or demonstrate complete epigenetic reversal. Emerging applications, including single\u2010cell and spatial epigenomics, tumour microenvironment deconvolution and CSF methylation profiling, remain investigational. Overall, DNA methylation profiling is most valuable when used as integrated diagnostic and risk\u2010stratification evidence within the complete histological, genomic and clinical context.\n                  <\/jats:p>","DOI":"10.1111\/nan.70100","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T07:01:26Z","timestamp":1787382086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DNA Methylation Profiling in IDH\u2010Mutant Gliomas: Biological Evolution, Molecular Grading and Clinical Implementation"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-3283","authenticated-orcid":false,"given":"Pietro","family":"Tralongo","sequence":"first","affiliation":[{"name":"Department of Biomedical, Dental, Morphological and Functional Imaging Sciences University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1349-0910","authenticated-orcid":false,"given":"Gabriele","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental, Morphological and Functional Imaging Sciences University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5638-0508","authenticated-orcid":false,"given":"Mariagiovanna","family":"Ballato","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Dental, Morphological and Functional Imaging Sciences University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1132-1761","authenticated-orcid":false,"given":"Vincenzo","family":"Fiorentino","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adults and Developmental Age \u201cGaetano Barresi,\u201d Division of Pathology University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3478-9217","authenticated-orcid":false,"given":"Valeria","family":"Zuccal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adults and Developmental Age \u201cGaetano Barresi,\u201d Division of Pathology University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-504X","authenticated-orcid":false,"given":"Giorgia","family":"Castellani","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore Di Sanit\u00e0, Viale Regina Elena 299  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2953-9291","authenticated-orcid":false,"given":"Quintino Giorgio","family":"D'Alessandris","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Fondazione Policlinico Universitario a. Gemelli IRCCS, Largo a. Gemelli, 8  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Fadda","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adults and Developmental Age \u201cGaetano Barresi,\u201d Division of Pathology University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Ricci\u2010Vitiani","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore Di Sanit\u00e0, Viale Regina Elena 299  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-0506","authenticated-orcid":false,"given":"Maria","family":"Caffo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Unit of Neurosurgery University of Messina  Messina 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